The essential fatty acids (EFAs) consist of a series of twelve compounds illustrated in Table 1 below. Although linoleic acid the parent compound of the n-6 series of EFAs, and alpha-linolenic acid the parent compound of the n-3 series, are usually the main dietary EFAs, these substances as such have relatively minor roles in the body. In order to be fully useful to the body, the parent compounds must be metabolized by the sequence of reactions shown in Table 1. In quantitative terms, as judged by their levels in cell membranes and in other lipid fractions, dihomo-gamma-linolenic acid (DGLA) and arachidonic acid (AA) are the main EFA metabolites of the n-6 series, while eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are the main metabolites of the n-3 series. DGLA, AA, EPA and DHA are important constituents of most of the lipids in the body. As well as being important in themselves they can also give rise to a wide range of oxygenated derivatives, the eicosanoids, including the prostaglandins, leukotrienes and other compounds.
The elongation reactions shown in Table 1, in which 2 carbon atoms are added to the chain, tend to be rapid, whereas the desaturation reactions in which an extra double bond is introduced tend to be very slow. Thus for example gamma-linolenic acid (GLA) is rapidly converted to DGLA while stearidonic acid is readily converted to 20:4n-3 and so these pairs of compounds are equivalent in dietary terms. However, DGLA is only slowly converted to AA. The reactions are not normally reversible nor, in man, are n-3 and n-6 series acids inter-convertible.
The table is as follows:
TABLE 1 ______________________________________ n-6 n-3 ______________________________________ 18:2 delta-9,12 18:3 delta-9,12,15 (linoleic acid) .vertline. (alpha-linolenic acid) delta-6 desaturase 18:3 delta-6,9,12 .dwnarw. 18:4 delta-6,9,12,15 (gamma-linolenic acid) .vertline. (stearidonic acid) elongation 20:3 delta-8,11,14 .dwnarw. 20:4 delta-8,11,14,17 (dihomo-gamma-linolenic .vertline. acid) delta-5 desaturase 20:4 delta-5,8,11,14 .dwnarw. 20:5 delta-5,8,11,14,17 (arachidonic acid) .vertline. (`eicosapentaenoic acid`) elongation 22:4 delta-7,10,13,16 .dwnarw. 22:5 delta-7,10,13,16,19 (adrenic acid) .vertline. delta-4 desaturase 22:5 delta-4,7,10,13,16 .dwnarw. 22:6 delta-4,7,10,13,16,19 (`docosahexaenoic acid`) ______________________________________
The acids, which in nature are of the all-cis configuration, are systematically named as derivatives of the corresponding octadecanoic, eicosanoic or docosanoic acids, e.g. delta-9, 12-octadecadienoic acid or delta-4,7,10,13,16, 19-docosahexaenoic acid, but numerical designations such as, correspondingly, 18:2 n-6 or 22:6 n-3 are convenient. Initials, for example, EPA for the 20:5 n-3 acid (eicosapentaenoic acid) or DHA for the 22:6 n-3 acid (docosahexaenoic acid), are also used but do not serve when n-3 and n-6 acids of the same chain length and degree of unsaturation exist as for example with the 22:5 acids. Trivial names in more or less common use in the n-6 series are as shown. Of the n-3 series only 18:3 n-3 has a commonly used trivial name, alpha-linolenic acid, though the name stearidonic acid is coming into use for the 18:4 n-3 acid and the names eicosapentaenoic acid and docosahexanenoic acid as such are also used.
Disease States
It is becoming apparent that in many different disease states there are abnormalities of EFA biochemistry leading to abnormal EFA levels in various lipid fractions and in various tissues. These diseases include diseases of the heart and circulation such as hypertension and coronary and peripheral vascular disease, diseases of inflammation and immunity such as atopic disorders, osteoarthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease and various disorders going under the general classifications of inflammatory or auto-immune, neurological disorders such as Alzheimer's disease, Parkinson's disease and multiple sclerosis, disorders of the kidney, disorders of the skin, disorders of the gastrointestinal tract, disorders of metabolism of calcium and other minerals, disorders of bone and connective tissue, disorders of the reproductive and endocrine systems, psychiatric disorders including schizophrenia, and disorders of aging.
It used to be thought sufficient, both in nutrition and in therapy of disease, to supply linoleic and alpha-linolenic acids and the body's own metabolism would invariably do the rest. It has now been evident for some time that this is not true. Different diseases have different abnormal patterns of EFAs and because of problems in metabolism these cannot be corrected simply by giving linoleic acid or alpha-linolenic acid. Many examples of this type of situation are given in papers and prior patents by the inventor. Relevant papers include Horrobin D.F. Rev. Contemporary Pharmacotherapy 1990: 1:1-41, Horrobin D.F. Progress Lipid Res 1992: 31: 163-194 and Horrobin D.F. and Manku M.S. pp. 21-53 in "Omega-6 Essential Fatty Acids" Ed. Horrobin, D.F. New York: Wiley-Liss, 1990
It is therefore desirable in some situations to give two or more of the EFAs simultaneously. For this purpose the EFAs may be divided into the following groups:
i) GLA and DGLA
ii) AA and its metabolites adrenic acid and the 22:5n-6 acid
iii) Stearidonic acid (SA) and the 20:4n-3 acid
iv) EPA and its metabolites the 22:5n-3 acid and DHA.
Moreover, the EFAs are exceptionally susceptible to oxidation and so it may be appropriate to co-administer the EFAs with oleic acid (OA) which has potent properties as an antioxidant.
While the EFAs can be supplied in various forms and in various mixtures, it is in principle convenient in both nutrition and in medical treatment to be able to supply the fatty acids as predetermined, particular molecules. This is particularly true with respect to pharmaceuticals, where regulations and directives covering combination products are becoming steadily more restrictive. For example, in order to win government approval for a combination drug product containing compounds A, B and C, it is now no longer adequate to mix the three compounds together in formulation X, and then to compare X with placebo, P. Many governments now require proof of the value of each individual chemical entity, whether or not the whole point of a proposal is a synergistic action of different entities or a newly discovered simultaneous lack of more than one entity. Therefore at the very least clinical studies have to be set up comparing P with X, with A alone, with B alone and with C alone. Some governments might also require comparisons with A+B, A+C and B+C. Thus at least five and possibly eight groups would be required for testing with an enormous escalation of cost. In order to avoid this situation, it would be appropriate instead of having a mixture of A, B and C, to have a single molecule in which A, B and C are found together in the same chemical compound, Y, allowing direct and simple testing of Y against P with only two groups required. For this purpose triglycerides, which can contain three fatty acids, are proposed.